Conclusion
Given that the amount of IL-1β modulates the severity of GAS infection, our results provide new insights into the effect of FH and internalised C4BP to control GAS sensing by inflammasomes.
Methods
The inflammasome response was investigated using primary human cells and the strain GAS-AP1. Cytokine responses were evaluated by ELISA. C4BP internalisation was investigated using confocal microscopy. Activation of the NLRP3 inflammasome components was assessed by Western blotting.
Results
Interleukin-1β (IL-1β) release, induced by GAS-AP1, was inhibited by FH which interferes with priming of human cells. In contrast, C4BP restricted the IL-1β response without affecting cell priming. C4BP was engulfed by cells together with bacteria and excluded from low-pH vesicles but localised within the cytosol and near the ASC speck inflammasome complex. C4BP did not inhibit either the inflammasome complex assembly or caspase-1 activation. However, C4BP limited the cleavage of gasdermin D N-terminal fragments by interfering with caspase-1 enzymatic activity.